Cancer signatures are robust characteristics distinguishing one entity from another, such as cancer cells from normal cells, or a recurrent cancer from a second primary tumor. Markers must leap a high bar to be considered a constituent of true cancer signatures. Mere over- or under-expression of a protein, for example, will not suffice. Cancer-specific signatures have wide potential utility as diagnostic aids, for monitoring of disease during therapy, for distinguishing true tumor resistance from second primaries, and as a target for immunotherapy and other clever therapeutic targeting. We can conceptualize protein signatures in the terminology of antigens and DNA signatures in terms of mutations! The early use of antigens as signatures was limited by bottlenecks, or research barriers. Many promising antigenic markers, such as EGFRvlll, were too infrequent to be practical in most tumor types. Others lacked stringent performance requirements, such as higher degrees of cancer-specificity, or a robust clonal expression among metastatic sites, or adequate evidence of antigen presentation suitable for therapeutic applications. Our recent preliminary data indicate that progressing past these bottlenecks can be achieved using new methods, data, and insights. Our short-term Aims are to identify cancer-specific proteins and neo-antigens, to determine the biological relevance of the identified proteins, and to evaluate the expression signatures in pancreatic cancer samples from patients using new antigenic tools we are developing. Our long-term goal is to enable a routine application of tumor-specific signatures for a more detailed data capture at diagnosis, individualized and efficacious treatment, clarity in the followup of disease course, and sensitive monitoring of therapeutic efficacy.